CERAMIDE SYNTHASE MEDIATES DAUNORUBICIN-INDUCED APOPTOSIS - AN ALTERNATIVE MECHANISM FOR GENERATING DEATH SIGNALS
CERAMIDE SYNTHASE MEDIATES DAUNORUBICIN-INDUCED APOPTOSIS - AN ALTERNATIVE MECHANISM FOR GENERATING DEATH SIGNALS
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DOI：
10.1016/0092-8674(95)90429-8
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发表时间：
1995-08-11
期刊：
影响因子：
64.5
通讯作者：
KOLESNICK, R
中科院分区：
文献类型：
--
作者：
BOSE, R;VERHEIJ, M;KOLESNICK, R
鞘磷脂途径由鞘磷脂水解启动，生成第二信使神经酰胺，向肿瘤坏死因子 α、Fas 和电离辐射发出细胞凋亡信号。在目前的研究中，抗癌药物柔红霉素还刺激 P388 和 U937 细胞中的神经酰胺升高和细胞凋亡。神经酰胺的细胞渗透类似物，但不是其他脂质第二信使，在诱导细胞凋亡方面模仿柔红霉素。然而，柔红霉素刺激的神经酰胺升高并非由鞘磷脂水解引起，而是由神经酰胺合酶激活从头合成所致。神经酰胺合酶的必然作用被确定，因为它的天然特异性抑制剂伏马菌素 B1 可以阻断柔红霉素诱导的神经酰胺升高和细胞凋亡。这些研究表明，神经酰胺合酶活性可以在真核生物中受到调节，并构成了诱导细胞凋亡需要神经酰胺升高的明确证据。
The sphingomyelin pathway, which is initiated by sphingomyelin hydrolysis to generate the second messenger ceramide, signals apoptosis for tu mor necrosis factor alpha, Fas, and ionizing radiation. In the present studies, the anticancer drug daunorubicin also stimulated ceramide elevation and apoptosis in P388 and U937 cells, Cell-permeable analogs of ceramide, but not other lipid second messengers, mimicked daunorubicin in inducing apoptosis. Daunorubicin-stimulated ceramide elevation, however, did not result from sphingomyelin hydrolysis, but rather from de novo synthesis via activation of the enzyme ceramide synthase. An obligatory role for ceramide synthase was defined, since its natural specific inhibitor, fumonisin B1, blocked daunorubicin-induced ceramide elevation and apoptosis. These studies demonstrate that ceramide synthase activity can be regulated in eukaryotes and constitute definitive evidence for a requirement for ceramide elevation in the induction of apoptosis.